Formula feeding often results in rapid weight gain and is a risk factor for pediatric and adult obesity. Rapid rates of growth during the first year of lie also increase risks for later metabolic syndrome and mortality from cardiovascular disease, leading some to argue that the focus should be on early life for both lifelong preventive interventions and further scientific inquiry. We recently discovered that one type of infant formula normalized weight gain of formula-fed infants relative to that of breastfed infants during the first year of life so we cannot consider formula-fed infants as a homogeneous group regarding the composition of the formula they feed, growth and consequent health outcomes. In a randomized, controlled trial, feeding a formula that consisted of extensively hydrolyzed protein (ePHF) resulted in weight-for-age and weight-for-length z-scores that followed the WHO growth standards (which are based on healthy breastfed infants), whereas the same measures in infants fed an isocaloric intact protein cow milk formula (CMF) were accelerated. The challenge is to understand the mechanisms underlying the effects of formula composition on energy balance and growth as a first step in providing practical alternatives that could be used to reduce obesity and related later-life risks in formula-fed infants. We propose to conduct a randomized trial of infants and their mothers during a 24-month window, manipulating the composition of the diet fed to infants. When the infants are 1 week of age and when the mothers' decision not to breastfeed is firmly established, infants will be randomized into groups that differ in the type of formula (ePHF, CMF) that the mothers will feed their infants during the first year of life. At fixed intervals during first 2 years of life, children will be weighed and measured to determine growth (energy deposition/storage). When they are 0.5, 3, and 12 months of age, energy balance will be determined by measuring its components: total and resting energy expenditure (Primary Aim 1), energy intake (Primary Aim 2), and energy loss in stool (Primary Aim 3). When the children are 3, 12, and 24 months, they will be videotaped while feeding their assigned formula, or solid foods, to satiation during child-led feeding sessions, after which biomarkers of satiation and satiety (active GLP-1 and ghrelin, respectively) and various measures of acceptance and hunger will be assessed (Secondary Aim 1). Anthropometric measures and food preferences will be obtained to explore whether and how later growth (Secondary Aim 2) and later diet and food preferences (Secondary Aim 3) based on early formula composition persists after children are weaned from formula. Because of the importance of early life for programming later-life health outcomes and for preventive intervention, this research examines highly pervasive and under-investigated phenomena surrounding energy balance and satiation related to diet in early life, in contrast to many other studies that attempt to relate diet composition and energy balance in older children and adults. The knowledge gained from this research will help provide practical alternatives to reduce obesity risk and improve the health of American infants who feed formula. PUBLIC HEALTH RELEVANCE: Formula feeding can result in rapid weight gain and is a risk factor for pediatric and adult obesity and other diseases. Modern infant formulas differ in protein quality and structure, and such differences significantly affect growth, so formula-fed infants are not a homogeneous group regarding the composition of the formula (diet) they feed and the consequent health outcomes. We propose a randomized trial to specify physiologic and behavioral mechanisms by which infant-formula composition affects energy balance and growth during the first two years of life. Because of the importance of early life for programming later-life health outcomes and for preventive intervention, the knowledge gleaned from this research may lead to practical alternatives to reduce obesity risk and improve the health of American infants who receive infant formula.